Pharmacokinetic modelling of caspofungin to develop an extended dosing regimen in paediatric patients.

BACKGROUND: Echinocandins are commonly used in treatment and prophylaxis of invasive fungal diseases. Intravenous daily dosing for prophylaxis in the outpatient setting can however become a hurdle for adequate compliance in the paediatric population. OBJECTIVES: Simulations were performed to assess extended twice-weekly dosing for antifungal prophylaxis using caspofungin. METHODS: A population pharmacokinetic model was developed based on previously published data from children aged 3 months to 17 years. Using the final model, Monte Carlo simulations were performed to assess the dose needed for adequate exposure in a twice-weekly setting. Mean weekly AUC0-24 h/MIC together with reported AUC0-24 h from previously reported paediatric trials were used to guide adequate exposure. RESULTS AND CONCLUSIONS: A two-compartment model with linear elimination and allometric scaling using fixed exponents was found most adequate to describe the given paediatric populations. Simulations showed that a 200 mg/m2 twice-weekly regimen with maximal 200 mg total dose should result in exposures matching registered daily dosing as well as commonly used pharmacokinetic/pharmacodynamic targets.

One size does not fit all: variations by ethnicity in demographic characteristics of men seeking fertility treatment across North America.

OBJECTIVE: To compare racial differences in male fertility history and treatment. DESIGN: Retrospective review of prospectively collected data. SETTING: North American reproductive urology centers. PATIENT(S): Males undergoing urologist fertility evaluation. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Demographic and reproductive Andrology Research Consortium data. RESULT(S): The racial breakdown of 6,462 men was: 51% White, 20% Asian/Indo-Canadian/Indo-American, 6% Black, 1% Indian/Native, <1% Native Hawaiian/Other Pacific Islander, and 21% "Other". White males sought evaluation sooner (3.5 ± 4.7 vs. 3.8 ± 4.2 years), had older partners (33.3 ± 4.9 vs. 32.9 ± 5.2 years), and more had undergone vasectomy (8.4% vs. 2.9%) vs. all other races. Black males were older (38.0 ± 8.1 vs. 36.5 ± 7.4 years), sought fertility evaluation later (4.8 ± 5.1 vs. 3.6 ± 4.4 years), fewer had undergone vasectomy (3.3% vs. 5.9%), and fewer had partners who underwent intrauterine insemination (8.2% vs. 12.6%) compared with all other races. Asian/Indo-Canadian/Indo-American patients were younger (36.1 ± 7.2 vs. 36.7 ± 7.6 years), fewer had undergone vasectomy (1.2% vs. 6.9%), and more had partners who underwent intrauterine insemination (14.2% vs. 11.9%). Indian/Native males sought evaluation later (5.1 ± 6.8 vs. 3.6 ± 4.4 years) and more had undergone vasectomy (13.4% vs. 5.7%). CONCLUSION(S): Racial differences exist for males undergoing fertility evaluation by a reproductive urologist. Better understanding of these differences in history in conjunction with societal and biologic factors can guide personalized care, as well as help to better understand and address disparities in access to fertility evaluation and treatment.

"The Back-up Vasectomy Reversal." Simultaneous Sperm Retrieval and Vasectomy Reversal in the Couple With Advanced Maternal Age: A Cost-Effectiveness Analysis.

OBJECTIVE: To determine the cost-effectiveness of different fertility options in men who have undergone vasectomy in couples with a female of advanced maternal age (AMA). The options include vasectomy reversal (VR), sperm retrieval (SR) with in vitro fertilization (IVF), and the combination of VR and SR with IVF, which is a treatment pathway that has been understudied. MATERIALS AND METHODS: Using TreeAge software, a model-based cost-utility analysis was performed estimating the cost per quality-adjusted life years (QALY) in couples with infertility due to vasectomy and advanced female age over a period of one year. The model stratified for female age (35-37, 38-40, >40) and evaluated four strategies: VR followed by natural conception (NC), SR with IVF, VR and SR followed by failed NC and then IVF, and VR and SR followed by failed IVF and then NC. QALY estimates and outcome probabilities were obtained from the literature and average patient charges were calculated from high-volume centers. RESULTS: The most cost-effective fertility strategy was to undergo VR and try for NC (cost-per-QALY: $7,150 (35-37 y), $7,203 (38-40 y), and $7,367 (>40 y)). The second most cost-effective strategy was the "back-up vasectomy reversal": undergo VR and SR, attempt IVF and switch to NC if IVF fails. CONCLUSION: In couples with a history of vasectomy and female of AMA, it is most cost-effective to undergo a VR. If the couple opts for SR for IVF, it is more cost-effective to undergo a concomitant VR than SR alone.

Treatment Trends and Cost Associated With Peyronie's Disease.

INTRODUCTION: Providers may use several treatment options for patients with Peyronie's disease; however, it is unclear whether practice patterns have evolved over recent years and if this has impacted cost. AIMS: To investigate trends in the treatment of Peyronie's disease over time and the associated costs using a national, commercial insurance claims database. METHODS: A retrospective cohort study was conducted using claims from the Truven MarketScan database from 2007 to 2018 for men with Peyronie's disease. Cost was estimated as either the sum of prescription oral or injectable treatment costs or as the single net cost associated with the operative procedure. MAIN OUTCOME MEASURES: Frequency of use of various treatments for Peyronie's disease and associated costs were assessed as trends over the timeline by year. RESULTS: The estimated annual incidence of Peyronie's disease in this population rose from 61 to 77 per 100,000 patients over the included years, and the percent annual treatment rate rose from 17.8% to 26.2%. Colchicine was the most commonly prescribed oral agent in 2007 used in 22% of treated individuals; by 2018, pentoxifylline was the most common prescribed oral agent used in 33%. In 2007, 11% of treated patients received intralesional verapamil; however, by 2018, 24% received injectable collagenase, whereas <1% received intralesional verapamil. The mean annual, per-individual cost of Peyronie's disease treatment increased from $1,531 in 2007 to $10,339 in 2018. The cost increase was greatest for injectable therapies, which rose from $811 per individual in 2007 to $16,184 in 2018, a 19-fold increase. CONCLUSIONS: Diagnosis and treatment of Peyronie's disease is increasing over time. Pentoxifylline has become the most common oral prescription, whereas injectable collagenase has become most common injection. The mean cost associated with Peyronie's disease treatment increased more than 5 times from 2007 to 2018 corresponding with Federal Drug Administration's approval of injectable collagenase. Loftus CJ, Rajanahally S, Holt SK, et al. Treatment Trends and Cost Associated With Peyronie's Disease. Sex Med 2020;8:673-678.

Core Recommendations for Antifungal Stewardship: A Statement of the Mycoses Study Group Education and Research Consortium.

In recent years, the global public health community has increasingly recognized the importance of antimicrobial stewardship (AMS) in the fight to improve outcomes, decrease costs, and curb increases in antimicrobial resistance around the world. However, the subject of antifungal stewardship (AFS) has received less attention. While the principles of AMS guidelines likely apply to stewarding of antifungal agents, there are additional considerations unique to AFS and the complex field of fungal infections that require specific recommendations. In this article, we review the literature on AMS best practices and discuss AFS through the lens of the global core elements of AMS. We offer recommendations for best practices in AFS based on a synthesis of this evidence by an interdisciplinary expert panel of members of the Mycoses Study Group Education and Research Consortium. We also discuss research directions in this rapidly evolving field. AFS is an emerging and important component of AMS, yet requires special considerations in certain areas such as expertise, education, interventions to optimize utilization, therapeutic drug monitoring, and data analysis and reporting.

Assessment of focused multivector ultraviolet disinfection withshadowless delivery using 5-point multisided sampling ofpatientcare equipment without manual-chemical disinfection.

BACKGROUND: The aim of this study was to evaluate the performance of a focused multivector ultraviolet (FMUV) system employing shadowless delivery with a 90-second disinfection cycle for patient care equipment inside and outside the operating room (OR) suite without manual-chemical disinfection. METHODS: A 5-point multisided sampling protocol was utilized to measure the microbial burden on objects inside and outside the OR environment in a 3-phase nonrandomized observational study. Surface sampling was performed pre- and postdisinfection in between cases (IBCs) to assess the performance of manual-chemical disinfection. FMUV system performance was separately assessed pre- and postdisinfection before the first case and IBCs. Additionally, visibly clean high-touch objects were sampled outside the OR, and the microbial burden reductions after FMUV disinfection were quantified without manual-chemical disinfection. RESULTS: Manual-chemical disinfection reduced the active microbial burden on sampled objects IBCs by 52.8%-90.9% (P < .05). FMUV reduced the active microbial burden by 92%-97.7% (P < .0001) before the firstcase and IBCs combined, and 96.3%-99.6% (P < .0001) on objects outside the OR without chemical disinfection. CONCLUSIONS: Five-point multisided sampling proved effective for assessing disinfection performance on all exterior sides of equipment. FMUV produced significant overall reductions of the microbial burden on patient care equipment in all study phases and independent of manual cleaning and chemical disinfection.

Use of secondary contraception following vasectomy: insights from the Pregnancy Risk Assessment Monitoring System, 2007-2011.

BACKGROUND: To assess postpartum use of secondary contraception with vasectomy within Pregnancy Risk Assessment Monitoring System (PRAMS). METHODS: Secondary contraception and type of method used were assessed among married women reporting partner vasectomy 4 months after a recent live birth in female residents of 15 US states and New York City who participated in the 2007-2011 PRAMS. RESULTS: Between 2007 and 2011, 1,004 married women who had a recent live birth participating in PRAMS reported they and their partners relied on vasectomy for postpartum contraception. Among these couples, 57.8% reported not using additional forms of contraception postpartum. Of those reporting additional contraception, condoms were most commonly used (50.0%), followed by oral contraceptive pills (26.5%), and withdrawal (9.5%). Multivariable modeling showed that use of secondary contraception was twice as high among women reporting a second birth versus women reporting a fourth or higher birth [adjusted prevalence odds ratio (POR) =2.0 (1.1-3.2)]. No other sociodemographic characteristics (maternal age, maternal race, parental education, household income) were significantly associated with use of secondary contraception with vasectomy. CONCLUSIONS: Most couples within PRAMS reporting partner vasectomy as postpartum contraception did not use secondary contraception in the months immediately after vasectomy, and, of those who did, most relied on less effective methods. Clinicians need to better understand reasons for limited use of secondary contraception with vasectomy to improve counseling strategies for reducing unintended pregnancy.

Exposure-Response Analysis of Micafungin in Neonatal Candidiasis: Pooled Analysis of Two Clinical Trials.

BACKGROUND: Neonatal candidiasis causes significant morbidity and mortality in high risk infants. The micafungin dosage regimen of 10 mg/kg established for the treatment of neonatal candidiasis is based on a laboratory animal model of neonatal hematogenous Candida meningoencephalitis and pharmacokinetic (PK)-pharmacodynamic (PD) bridging studies. However, little is known about the how these PK-PD data translate clinically. METHODS: Micafungin plasma concentrations from infants were used to construct a population PK model using Pmetrics software. Bayesian posterior estimates for infants with invasive candidiasis were used to evaluate the relationship between drug exposure and mycologic response using logistic regression. RESULTS: Sixty-four infants 3-119 days of age were included, of which 29 (45%) infants had invasive candidiasis. A 2-compartment PK model fits the data well. Allometric scaling was applied to clearance and volume normalized to the mean population weight (kg). The mean (standard deviation) estimates for clearance and volume in the central compartment were 0.07 (0.05) L/h/1.8 kg and 0.61 (0.53) L/1.8 kg, respectively. No relationship between average daily area under concentration-time curve or average daily area under concentration-time curve:minimum inhibitory concentration ratio and mycologic response was demonstrated (P > 0.05). Although not statistically significant, mycologic response was numerically higher when area under concentration-time curves were at or above the PD target. CONCLUSIONS: While a significant exposure-response relationship was not found, PK-PD experiments support higher exposures of micafungin in infants with invasive candidiasis. More patients would clarify this relationship; however, low incidence deters the feasibility of these studies.

The rise of hospitalists: an opportunity for infectious diseases investigators.

INTRODUCTION: Despite the essential role played by infectious diseases specialists in patient care, public health, cost-containment, and biomedical research, the field has a substantially higher percentage of vacant positions than other medicine sub-specialties. While much has been written about what this disturbing trend means for patient care, comparatively little attention has been focused on the dire implications for clinical research and the development of novel anti-infective therapy. Areas covered: We examine the ways that hospitalists and infectious disease specialists might collaborate to study emerging diagnostic platforms, novel antimicrobial agents, and strengthen antimicrobial stewardship programs to improve the delivery of high-quality health care. Through the use of PubMed, the manuscript reviews existing collaborations as well as those that might develop in the years to come. Expert commentary: In this paper, we propose potential strategies to confront this emerging problem, focusing on novel collaborations with the hospitalist - the specialist in inpatient medicine - to bolster the pipeline of funding for clinical infectious diseases investigators.

Evaluation of Vasectomy Trends in the United States.

OBJECTIVE: To use the Truven Health MarketScan database to better approximate the annual rate of vasectomies performed in the US population, to determine changes over time, regional differences, providers performing this, and to know if there is any monthly variation in vasectomy rates. MATERIALS AND METHODS: Claims data were evaluated from 2007 to 2015 to determine the annual prevalence of vasectomy by patient age and region in the United States. The cohort included men aged 18-64 years with at least 1 claim in any given year in Truven Health MarketScan. Provider type and place of service were evaluated in 2014 and 2015. Monthly evaluation of vasectomy prevalence compared with total claims was performed. RESULTS: The prevalence of vasectomies decreased from 2007 to 2015, across all age groups and in all locations of the country (P <.001). Using these data and the most recent US census data, an estimated 527,476 vasectomies were performed in the United States in 2015. The North Central and West regions (0.64% and 0.60%, respectively) had the highest annual prevalence of vasectomies. The month of March and the end of the year had the highest proportion of vasectomies performed. In both 2014 and 2015, a urologist in the office setting performed 82% of vasectomies. CONCLUSION: An estimated 527,476 vasectomies were performed in the United States in 2015. From 2007 to 2015 there was a decrease in the proportion of vasectomies performed in all age groups and in all locations of the country. The end of the year and the month of March are when the most vasectomies are performed.

Endpoint Assessment in Rabbit Models of Invasive Pulmonary Aspergillosis and Mucormycosis.

Multiple animal models have been developed to study the pathogenesis of invasive pulmonary aspergillosis, as well as to evaluate the efficacy, pharmacokinetics, and pharmacodynamics of various antifungal agents and vaccines. Each model is beneficial depending on the questions that are asked. In this chapter, we will discuss the endpoints assessment of the persistently neutropenic rabbit models of invasive pulmonary aspergillosis and invasive pulmonary mucormycosis.

Pharmacodynamics of isavuconazole in experimental invasive pulmonary aspergillosis: implications for clinical breakpoints.

OBJECTIVES: Isavuconazole, a novel triazole antifungal agent, has broad-spectrum activity against Aspergillus spp. and other pathogenic fungi. The isavuconazole exposure-response relationship in experimental invasive pulmonary aspergillosis using galactomannan index (GMI) suppression as a marker of disease clearance was explored. METHODS: The impact of exposure on GMI suppression in persistently neutropenic rabbits treated with isavuconazonium sulphate (isavuconazole-equivalent dosages of 20, 40 or 60 mg/kg every 24 h, after a 90 mg/kg loading dose) for 12 days was linked using mathematical modelling. Bridging to humans using population pharmacokinetic (PK) data from a clinical trial in invasive aspergillosis was performed using Monte Carlo simulations. RESULTS: Mean plasma isavuconazole AUC/MIC (EC50) of 79.65 (95% CI 32.2, 127.1) produced a half-maximal effect in GMI suppression. The inhibitory sigmoid Emax curve dropped sharply after an AUC/MIC of ≥30 and was near maximum (EC80) at ∼130. Bridging the experimental PK/pharmacodynamic (PD) target to human population PK data was then used to return to the rabbit model to determine a clinically relevant PD endpoint. The clinical dosing regimen used in the trial would result in a mean GMI of 4.3 ±â€Š1.8, which is a 50% reduction from the starting GMI in the experiment. CONCLUSIONS: The clinical trial results showing the non-inferiority of isavuconazole to voriconazole for all-cause mortality further support the PK-PD endpoint, thereby demonstrating the usefulness of the rabbit model and endpoint for isavuconazole and implications on interpretive breakpoints. Importantly, the analysis supports this model as an important tool for development of antifungal agents.

Testicular fine-needle aspiration for the assessment of intratesticular hormone concentrations.

Measurement of intratesticular sex steroid concentrations in men informs both the development of male hormonal contraceptives and the understanding of male infertility. Given the challenges of using invasive techniques to measure testicular hormone physiology, our group has used a minimally-invasive fine-needle aspiration technique to measure intratesticular hormones in normal healthy men. Herein, we present a post-hoc analysis of the safety and efficacy of testicular fine-needle aspiration (FNA) completed as part of six clinical trials. From 2001 through 2011, a total of 404 procedures were conducted among 163 research volunteers, 85.9% of which were successful in obtaining sufficient fluid for the measurement of intratesticular steroid concentrations. Pain was the most common side effect, with 36.8% of procedures associated with moderate procedural pain and 4.7% with severe procedural pain. Postprocedural pain was uncommon and abated within a few days. Mild local bruising occurred with 14.9% of procedures. Two serious adverse events (0.5%) required surgical intervention. The risk of an adverse event was not associated with age, body mass index, testicular size, or the volume of fluid aspirated. Testicular FNA to obtain fluid for measurement of intratesticular steroid concentrations frequently causes mild to moderate procedural pain, but serious adverse events occur rarely. Testicular FNA has been instrumental for defining human intratesticular hormone physiology and is a minimally-invasive, safe, effective method for obtaining fluid for research on testicular physiology and pathology.

Pharmacodynamics of amphotericin B deoxycholate, amphotericin B lipid complex, and liposomal amphotericin B against Aspergillus fumigatus.

Amphotericin B is a first-line agent for the treatment of invasive aspergillosis. However, relatively little is known about the pharmacodynamics of amphotericin B for invasive pulmonary aspergillosis. We studied the pharmacokinetics (PK) and pharmacodynamics (PD) of amphotericin B deoxycholate (DAMB), amphotericin B lipid complex (ABLC), and liposomal amphotericin B (LAMB) by using a neutropenic-rabbit model of invasive pulmonary aspergillosis. The study endpoints were lung weight, infarct score, and levels of circulating galactomannan and (1 → 3)-ß-D-glucan. Mathematical models were used to describe PK-PD relationships. The experimental findings were bridged to humans by Monte Carlo simulation. Each amphotericin B formulation induced a dose-dependent decline in study endpoints. Near-maximal antifungal activity was evident with DAMB at 1 mg/kg/day and ABLC and LAMB at 5 mg/kg/day. The bridging study suggested that the "average" patient receiving LAMB at 3 mg/kg/day was predicted to have complete suppression of galactomannan and (1 → 3)-ß-D-glucan levels, but 20 to 30% of the patients still had a galactomannan index of >1 and (1 → 3)-ß-D-glucan levels of >60 pg/ml. All formulations of amphotericin B induce a dose-dependent reduction in markers of lung injury and circulating fungus-related biomarkers. A clinical dosage of liposomal amphotericin B of 3 mg/kg/day is predicted to cause complete suppression of galactomannan and (1 → 3)-ß-D-glucan levels in the majority of patients.

Aspergillus osteomyelitis: epidemiology, clinical manifestations, management, and outcome.

BACKGROUND: The epidemiology, pathogenesis, diagnosis, and management of Aspergillus osteomyelitis are not well understood. METHODS: Protocol-defined cases of Aspergillus osteomyelitis published in the English literature were reviewed for comorbidities, microbiology, mechanisms of infection, clinical manifestations, radiological findings, inflammatory biomarkers, antifungal therapy, and outcome. RESULTS: Among 180 evaluable patients, 127 (71%) were males. Possible predisposing medical conditions in 103 (57%) included pharmacological immunosuppression, primary immunodeficiency, and neutropenia. Seventy-three others (41%) had prior open fracture, trauma or surgery. Eighty (44%) followed a hematogenous mechanism, 58 (32%) contiguous infections, and 42 (23%) direct inoculation. Aspergillus osteomyelitis was the first manifestation of aspergillosis in 77%. Pain and tenderness were present in 80%. The most frequently infected sites were vertebrae (46%), cranium (23%), ribs (16%), and long bones (13%). Patients with vertebral Aspergillus osteomyelitis had more previous orthopedic surgery (19% vs 0%; P = 0.02), while those with cranial osteomyelitis had more diabetes mellitus (32% vs 8%; P = 0.002) and prior head/neck surgery (12% vs 0%; P = 0.02). Radiologic findings included osteolysis, soft-tissue extension, and uptake on T2-weighted images. Vertebral body Aspergillus osteomyelitis was complicated by spinal-cord compression in 47% and neurological deficits in 41%. Forty-four patients (24%) received only antifungal therapy, while 121 (67%) were managed with surgery and antifungal therapy. Overall mortality was 25%. Median duration of therapy was 90 days (range, 10-772 days). There were fewer relapses in patients managed with surgery plus antifungal therapy in comparison to those managed with antifungal therapy alone (8% vs 30%; P = 0.006). CONCLUSIONS: Aspergillus osteomyelitis is a debilitating infection affecting both immunocompromised and immunocompetent patients. The most common sites are vertebrae, ribs, and cranium. Based upon this comprehensive review, management of Aspergillus osteomyelitis optimally includes antifungal therapy and selective surgery to avoid relapse and to achieve a complete response.

Comparative cost-effectiveness analysis of voriconazole and fluconazole for prevention of invasive fungal infection in patients receiving allogeneic hematopoietic cell transplants.

PURPOSE: The cost-effectiveness of voriconazole versus fluconazole prophylaxis against fungal infections in hematopoietic cell transplant (HCT) recipients is investigated. METHODS: A decision-analytic model was developed to estimate the drug costs associated with planned or supplemental prophylaxis and empirical therapy and the costs of treating suspected or documented invasive fungal infections (IFIs) in HCT recipients. Published clinical trial data on 599 patients who received 100-180 days of prophylactic therapy with voriconazole or fluconazole were used to model specified IFI-prevention and mortality outcomes; 6-month, 12-month, and lifetime incremental cost-effectiveness ratios (ICERs) were estimated, with a bootstrap analysis performed to reffect the uncertainty of the clinical trial data. RESULTS: Estimated mean total prophylaxis and IFI-related costs associated with voriconazole versus fluconazole prophylaxis over 12 months were higher in the entire study population and among patients receiving HCT for diagnoses other than acute myeloid leukemia (AML) but were not significantly different for patients with AML. The cost per IFI avoided ($66,919) and the cost per life-year gained ($5,453) were lower among patients with AML who received voriconazole relative to the full study population. ICERs were more favorable for voriconazole over a 6-month time frame and when modeling was conducted using generic price data. Assuming a threshold value of $50,000 for one year of life gained, the calculated probability of voriconazole being cost-effective was 33% for the full study population and 85% for the AML subgroup. CONCLUSION: The decision model indicated that voriconazole prophylaxis was cost-effective for patients undergoing allogeneic HCT for AML.

Validity and reliability of a smartphone application for the assessment of penile deformity in Peyronie's disease.

INTRODUCTION: Available methods to evaluate men with Peyronie's disease (PD) are limited by the inability to accurately and reproducibly measure penile deformity. AIM.: The study aims to evaluate the performance of a smartphone application for the measurement of penile curvature and narrowing. METHODS: A smartphone application, the University of Washington Peyronie's Examination Network (UWPEN), was developed for this purpose. To assess penile curvature, 15 single cylinders of malleable penile prostheses were molded to varying curvature angles. Three blinded observers nonsequentially measured the angle of curvature for each prosthetic cylinder using a protractor, goniometer, and UWPEN. To assess girth narrowing, six clay models of the penile shaft were constructed to represent conditions of normal, partial hourglass, circumferential hourglass, and pencil narrowing. Girth was measured using a ruler and UWPEN by the same blinded observers. MAIN OUTCOME MEASURES: Statistical analyses compared intertest, interobserver, and intraobserver reliability using the interclass correlation coefficient (ICC). An ICC above 0.75 indicates excellent reproducibility among measurements. RESULTS: Intertest reliability for angle measurements yielded an ICC for the three methods of 1.000. Separately, the ICC for UWPEN vs. the goniometer and protractor was 0.999 and 0.999, respectively. The interobserver ICC for UWPEN, goniometer, and protractor was 0.998, 0.999, and 1.000, respectively. Intertest reliability for girth narrowing measurements yielded an ICC of 0.991. The interobserver ICC for girth narrowing for UWPEN and the ruler was 0.978 and 0.986, respectively. Intraobserver ICC for angle measurements and girth narrowing showed high reliability for all observers and methods. CONCLUSIONS: The performance of UWPEN is comparable with and highly correlated with angle measurements obtained from the goniometer and protractor as well as with girth narrowing measurements obtained from a ruler. Measurements are reproducible among different observers. UWPEN may provide a noninvasive, accurate, reliable, and widely accessible method to characterize and track PD over time.

Anidulafungin for neonatal hematogenous Candida meningoencephalitis: identification of candidate regimens for humans using a translational pharmacological approach.

Hematogenous Candida meningoencephalitis (HCME) is a serious infection in premature neonates. Anidulafungin is an echinocandin antifungal agent with potent activity against Candida spp., but its efficacy and optimal regimens for human neonates with HCME are not known. A well-validated rabbit model of HCME was used to define pharmacokinetic-pharmacodynamic (PK-PD) relationships of anidulafungin. A mathematical model was fitted to the entire data set. The experimental data were bridged to humans. A population PK model was fitted to the data from human neonates receiving anidulafungin receiving a loading dose of 3 mg/kg, followed by 1.5 mg/kg/day. Monte Carlo simulations were performed to identify candidate anidulafungin regimens for humans. All untreated rabbits succumbed by ≤96 h postinoculation. The PK of anidulafungin was linear with dose-dependent penetration into the cerebrum. Anidulafungin exerted a rapid antifungal effect that was apparent in the first dosing interval. Near-maximal antifungal activity was observed with dosages of 10 to 20 mg/kg/day. The bridging studies suggested that the current regimen of first 3 mg/kg, followed by 1.5 mg/kg/day, is suboptimal. Higher dosages were associated with progressively greater antifungal effect. Anidulafungin is effective for the treatment of experimental HCME. Higher dosages than those currently used for clinical care are required for maximal antifungal effect.

Socioeconomic disparities in the use and success of fertility treatments: analysis of data from a prospective cohort in the United States.

OBJECTIVE: To determine the effect of income, education, and race on the use and outcomes of infertility care. DESIGN: Prospective cohort. SETTING: Eight community and academic infertility practices. PATIENT(S): Three hundred ninety-one women presenting for an infertility evaluation. INTERVENTION(S): Face-to-face and telephone interviews and questionnaires. MAIN OUTCOME MEASURE(S): Use of infertility services and odds of pregnancy. Linear and logistic regression used to assess relationship between racial and socioeconomic characteristics, use of infertility services, and infertility outcomes. RESULT(S): After adjustment for age and demographic and fertility characteristics, college-educated couples (ß = $5,786) and households earning $100,000-$150,000 (ß = $6,465) and ≥$150,000 (ß = $8,602) spent significantly more on infertility care than their non-college-educated, lower-income counterparts. Higher income and college-educated couples were much more likely to use more cycles of higher-intensity fertility treatment. The increased cost of infertility care was primarily explained by these differences in number and type of infertility treatment. Even after adjustment for these factors and total amount spent on fertility care, having a college degree was associated with persistently higher odds of achieving a pregnancy (OR = 1.9). CONCLUSION(S): Education and household income were independently associated with the amount of money spent on fertility care. This relationship was primarily explained by types and intensity of infertility treatments used. Having at least a college degree was independently associated with improved odds of pregnancy.

Population pharmacokinetics of micafungin in neonates and young infants.

Micafungin is an echinocandin with potent activity against Candida spp. Hematogenous Candida meningoencephalitis (HCME) is a frequent complication of disseminated Candida infection in premature infants. A preclinical model of HCME suggests that micafungin may be an effective agent for this syndrome, but relatively high weight-based dosages are required. This prompted the further study of the safety and pharmacokinetics (PK) of micafungin in infants. Here, we describe the population pharmacokinetics of micafungin in 47 infants with a proven or presumptive diagnosis of disseminated candidiasis, who received 0.75, 1.5, 3, 7, 10, and 15 mg/kg of micafungin. The drug was infused daily, and samples were taken in the first dosing interval and at steady state. Serum concentrations were measured using high-performance liquid chromatography (HPLC). Data were modeled using an allometric pharmacokinetic model using a three-fourths scaling exponent for clearance and parameters normalized to a 70-kg adult. Drug exposures were estimated using Monte Carlo simulation. Optimal sampling times were determined using D-optimal design theory. The fit of the allometric model to the data was highly acceptable. The pharmacokinetics of micafungin were linear. The weight-normalized estimates of clearance and volume of distribution approximated those previously described for adults. The original population parameter values could be recapitulated in the Monte Carlo simulations. A dosage of 10 mg/kg/day resulted in 82.6% of patients with areas under the concentration-time curve (AUCs) that are associated with near-maximal decline in fungal burden within the central nervous system (CNS).